Foot-and-mouth disease (FMD) is a usually acute disease affecting cloven-hoofed domestic and wild animals like cattle, buffalo, sheep, deer, and pigs. The disease is associated with a high morbidity and low mortality. Subclinical and persistent infections occur and pose major problems for disease control. The virus is highly contagious and is transmitted by contact with infected animals and contaminated materials, humans, and non-susceptible animals. Over the past twenty years, FMD has been endemic in large areas of Asia, Africa, Southern America, and occasionally Europe, but not in Australia and Northern America. Disease control measures often included massive culling. This strategy has received intense criticism. Current vaccines for FMD are readily available and safe; however, due to the complex production process and other drawbacks they are not employed as a universal and global weapon against FMD.
Outbreaks of FMD result in devastating and drastic consequences for both animals and humans. Affected countries suffer from substantial loss in livestock and animal products, and in export markets, both short- and long-term. Additional costs, distress and suffering arise from eradication measurements, compensation policies, and disruption of normal living.
Vaccination against FMDV is an established and specific tool to help control both FMD eradication and outbreaks. Definitive strategies, however, do not exist and depend on a broad range of implications. There are no antiviral treatments for FMDV.
FMDV is an antigenically variable virus consisting of seven serotypes (European types A, O and C; African types SAT1, SAT2 and SAT3; and an Asiatic type Asia 1) and dozens of subtypes (see for example Kleid et al., 1981, Science 214: 1125-1129). Immunity to one serotype does not provide protection against the others and in some cases, immunity to one subtype will not protect against other members of the same subtype. Currently used vaccines consist of tissue culture grown virus, which for some preparations are partially purified and which are typically inactivated by binary ethyleneimine (BEI).
Modern FMD vaccines, in combination with other measures, can be used to contain and eradicate FMD outbreaks. Contact transmission of FMDV is rapidly reduced within 3-5 days after vaccination of pigs, cattle, sheep, and other animals.
However, some concerns exist over the use of FMD vaccines. After exposure to FMDV, vaccination may only prevent disease but not infection, and some animals may become persistently infected carriers of FMDV. Using approved diagnostic tests, it is difficult, if not impossible to differentiate vaccinated from infected or convalescent animals. Based on the current technology, production of vaccines requires handling of live virus in high containment facilities, which excludes countries such as the USA from vaccine production.
US Published Patent Application 2004/0001864 teaches a vaccine against foot-and-mouth disease wherein empty capsids are produced by coexpressing P1 and protease 3C.
U.S. Pat. No. 5,864,008 teaches a Th-cell epitope derived from VP3 capsid protein of FMDV.
U.S. Pat. No. 5,612,040 teaches a foot-and-mouth disease vaccine comprising deletion of the G-H loop of VP1 which results in an antigenic but non-infectious virus.
U.S. Pat. No. 5,824,316 teaches a genetically engineered foot-and-mouth disease virus wherein the leader proteinase has been deleted. The L proteinase-deleted viruses are able to assemble and grow in cells in culture, but are less toxic to infected cells within the cells, thereby producing an attenuated infection.
U.S. Pat. No. 6,048,538 teaches the use of immunodominant domains from FMDV non-structural proteins 3A, 3B and 3C and the use thereof for detecting anti-FMDV antibodies in animal body fluids.
Published US Patent Application 2003/0171314 teaches early protection of susceptible animals against FMDV by inoculating the animals with a vaccine comprising an interferon DNA sequence and optionally a foot-and-mouth disease vaccine.
U.S. Pat. No. 6,107,021 teaches a peptide composition comprising at least one target antigenic site derived from VP1 capsid protein of FMDV covalently linked to a helper T cell epitope.
Published PCT Application WO 03/083095 teaches insertion of a heterologous sequence between two furin cleavage sites within a carrier glycoprotein, such as the furin cleavage sites of an F protein of a Respiratory Syncytial Virus and using the resulting mutant virus as a multivalent vaccine.
Published US Patent Application 2004/0001864 teaches the preparation of empty FMDV capsids by expression of the P1 region and protease 3C. Mason et al. (Vaccines for OIE List A and Emerging Animal Diseases, 2003, Brown and Roth eds, Dev Biol Base1, Karger, vol 114: 79-88) teaches a similar method, involving the expression of a fragment of the P1 region and protease 3C for producing empty capsids.
Structures on the surface of the virus particle present antigenic sites that are important for the immune response to FMDV. In particular, fragments derived from surface peptide 1D elicit neutralizing antibodies that could protect animals from challenge. However, when used alone, 1D-based vaccines failed to induce sufficient immunity in challenge experiments. In general, the entire accessible surface of a virus would be expected to be antigenic and may thus assist in the generation of a strong immunity. Specific formulations of all, recombinantly expressed non-infectious FMDV capsid proteins appear to be as efficacious as a commercial vaccine, with regard to immunogenicity and resistance to challenge with FMDV.